Scientists have completed the first human clinical trial of a recombinant vaccine for the deadly toxin ricin – a potential bioterror threat – and the results indicate the vaccine is safe and effective in eliciting ricin-neutralizing antibodies, the UT Southwestern Medical Center researchers report.

The nearly year-long pilot study involved three groups of five volunteers each. Individuals in each group received a series of three injections of various doses of the vaccine, called RiVax, over the study period. As a recombinant vaccine, RiVax is a form of ricin that consists of a genetically modified subunit of the toxin, rather than an inactivated whole toxin.

All five of the individuals in the group receiving the highest vaccine dose produced ricin-neutralizing antibodies in their blood, indicating their immune systems had responded. Four of five in the intermediate dose group produced antibodies, while one of five in the lowest dose group did so.

The human-produced antibodies were then injected along with active ricin toxin into test mice, and the mice survived.

The results of the vaccine trial will be available this week online and in an upcoming issue of the Proceedings of the National Academy of Sciences.

"Our major concern in this trial was safety," said Dr. Ellen Vitetta, director of the Cancer Immunobiology Center at UT Southwestern and lead author of the study. "We have taken a very deadly toxin and genetically engineered it to be safe and to induce protective immunity in humans."

Dr. Vitetta's work with ricin received international attention when she and a team of UT Southwestern researchers in the Cancer Immunobiology Center developed the experimental vaccine for the deadly toxin as an outgrowth of their cancer-therapy work. Dr. Vitetta, Dr. Joan Smallshaw, assistant professor in the center, and their colleagues showed in pre-clinical studies that the subunit of the ricin toxin used to make RiVax was non-toxic but retained the capacity to elicit immunity.

Ricin, which can be administered in food and water or sprayed as an aerosol, is extracted from castor beans. There is currently no approved vaccine to prevent ricin poisoning in humans, and the biological agent has a long history of use in espionage.

Participants in the study, however, reported only mild side effects that were consistent with any intramuscular vaccine injection, such as a sore arm or mild headache that might be experienced with a tetanus or a flu shot, said Dr. Robert Munford, a professor of internal medicine and a collaborator on the study.

Based on the protection they observed in the mice injected with ricin mixed with human-produced antibodies, the researchers projected that a RiVax-vaccinated human could withstand a lethal dose of injected ricin. According to the Centers for Disease Control and Prevention, such a dose for an adult is as little as approximately 500 micrograms of ricin, an amount that would fit on the head of a pin.

The results from the UT Southwestern trial justify further development of the vaccine, Dr. Vitetta said.

"We have shown that this vaccine is safe and immunogenic," said Dr. Vitetta. "Now we need to tinker with the dose and formulation to give the longest-lasting and most robust immunity."

Antibodies were present in the blood of study participants for as long as 127 days after the last vaccine injection, but the longevity of the antibodies in a given volunteer was not related to the dose level of the vaccine he or she received. Dr. Vitetta and her colleagues are now conducting studies on mice that combine the vaccine with an adjuvant, a formulation that may lengthen the time the vaccine is effective. An adjuvant, such as alum, is an ingredient that enhances the immune response of a stand-alone vaccine. Other common vaccines, such as tetanus, are typically administered with an adjuvant and can confer immunity for years.

Dr. Smallshaw is currently determining whether the vaccine protects against aerosol and oral administrations in mice. "In a recent series of experiments, we have shown that the vaccine protects mice against lethal doses of ricin administered orally just as well as it protects them against injected ricin," she said. "We are also setting up an aerosol challenge model to determine the protective benefits of the vaccine."

Dr. Vitetta noted that, in humans, exposure by aerosol or food may require inducing immunity in the lung and gut by a very different formulation and vaccination schedule.

Depending on how the ricin is administered as a poison, victims develop fever, nausea and abdominal pain or lung damage before dying within a few days of exposure. There is no antidote after the first few hours of exposure and, because symptoms do not appear until later and often mimic other illnesses, individuals often do not know if they have been exposed until it is too late for treatment, Dr. Vitetta said.

Because castor beans are readily available – more than 50,000 tons of castor bean extract exist around the world as a byproduct of castor oil production – public health officials warn that ricin could be used for terrorism. Indeed, there have been several incidents in recent years involving the toxin in the United States and Europe. The CDC classifies ricin as a "Category B" biological agent, which means it is "relatively easy to disseminate."

DOR BioPharma has received an exclusive license for RiVax and is developing large scale manufacturing processes. DOR officials hope to produce a large stockpile for more advanced human clinical testing, product licensing and potential purchases from the U.S. government and other interested parties.

Other UT Southwestern researchers from the Cancer Immunobiology Center involved in the study were Dr. John Schindler, assistant professor and director of clinical trials, and Dr. Elaine Coleman, senior research associate. Dr. Hasan Jafri, assistant professor of pediatrics, and Callie Foster, senior research nurse, also participated.